Compulsory drug seeking and consumption is a defining feature of cocaine dependence. Underlying such compulsory behaviors exists a core impairment in inhibitory control. Despite abundant behavioral evidence for impaired inhibitory control in patients with cocaine dependence (PCD), the neural processes underlying such a deficit remain unknown. The current application fills this important gap by using a stop signal task (SST), in which successful performance requires prepotent, habitual behaviors (as in compulsory drug seeking) to be inhibited. In previous work we observed that response readiness and error monitoring influence stop signal inhibition. In a functional magnetic resonance imaging (fMRI) study, we showed that the superior medial frontal and cingulate cortices activate during response inhibition. While the superior medial frontal activation dictates motor performance, cingulate activation appears to be performance- invariant. Moreover, PCD did not differ from healthy control subjects either in stop signal performance or regional brain activation when these task-related factors were considered. Based on these results, we hypothesize that the PCD exhibit deficits in response inhibition only when they are in a state of reward craving. We propose to test this hypothesis directly by conducting an fMRI study in which methylphenidate is used to induce reward craving. We will compare stop signal performance and regional brain activation in forty non-treatment-seeking PCD in two fMRI sessions on separate days. They receive placebo and methylphenidate injection each in the two sessions, with the order of injection counterbalances across subjects. With this intra-subject design, the project addresses two specific aims. First, do PCD demonstrate impaired stop signal performance during the methylphenidate, compared to the placebo session? Second, do PCD demonstrate altered regional brain activation during the methylphenidate, compared to the placebo session? If yes, which brain areas demonstrate performance- invariant differences? These potential results would provide an innovative approach to study cognitive inhibitory control in PCD and facilitate the development of novel pharmacotherapy that targets the "braking mechanism" in cocaine dependence. Cocaine dependence is a chronic, relapsing disorder. Patients with cocaine dependence oftentimes report that they understand the serious consequences of using cocaine, but they are not able to "control" their behaviors. One of the major goals of addiction neuroscience is thus to understand how our brain exercises inhibitory control and monitor our behaviors and how these processes are altered in the patients of cocaine dependence. The goal of this application is to combine functional brain imaging with a behavioral task as a cognitive proxy to examine these issues. The results gathered from the proposed projects will help us understand the "cocaine-dependent brain" and facilitate the development of novel therapeutic strategies to treat patients with cocaine dependence. [unreadable] [unreadable] [unreadable]